This invention relates to novel compositions of matter containing optically pure (-) pantoprazole. These compositions possess potent activity in treating ulcers of the stomach, duodenum and esophagus, gastroesophageal reflux diseases, Zollinger-Ellison Syndrome, and other disorders including those that would benefit from an inhibitory action on gastric acid secretion. (-) Pantoprazole inhibits the H.sup.+, K.sup.+ -ATPase associated with the gastric proton pump and the resulting secretion of gastric acid by parietal cells providing therapy in diseases associated with gastric hyperacidity. Optically pure (-) pantoprazole provides this treatment while substantially reducing adverse effects, including, but not limited to, hepatocellular neoplasia, gastrin hypersecretion, gastric neoplasms or carcinoids, headache, diarrhea and skin alterations which are associated with the administration of the racemic mixture of pantoprazole. Also disclosed are methods for treating the above described conditions in a human while substantially reducing the adverse effects that are associated with the racemic mixture of pantoprazole by administering the (-) isomer of pantoprazole to said human.
The active compound of these compositions and methods is an optical isomer of pantoprazole. The preparation of racemic pantoprazole is described in U.S. Pat. No. 4,758,579. The medicinal chemistry of pantoprazole is described by Kohl et al. J. Med. Chem. 35, 1049-1057 (1992)!, Kromer et al. J. Pharm. Exp. Ther. 254, 129-135 (1990)!, Simon et al. Aliment. Pharmacol. Therap. 4, 239-245 (1990)!, Beil et al. Europ. J. Pharmacol. 218, 265-271 (1992)!, and Kromer et al. Pharmacology 41, 333-337 (1990)!. Chemically, the active compound is the (-) isomer of 5-(difluoromethoxy)-2-3,4-dimethoxy-2-pyridinyl)methyl!sulfinyl!-1H-benz imidazole(I), hereinafter referred to as pantoprazole. ##STR1##
(-) Pantoprazole, which is the subject of the present invention, is not presently commercially available; only the 1:1 racemic mixture is commercially available as its sodium salt.
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. There is no correlation between nomenclature for the absolute stereochemistry and for the rotation of an enantiomer. Thus, D-lactic acid is the same as (-) lactic acid, and L-lactic acid is (+). For a given chemical structure, these chiral compounds exist as a pair of enantiomers which are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of the beta-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer has been believed to be a potent teratogen.
The separation of racemic pantoprazole into (+) pantoprazole and (-) pantoprazole is described in German application 4,035,455, but no pharmacology of the individual enantiomers is reported.
Racemic pantoprazole had been in clinical trials in Europe and the United States under the sponsorship of two pharmaceutical manufacturers, but the United States and British sponsor withdrew in 1991 due to concerns about hepatocellular neoplasia seen in rats in a two year carcinogenicity study. Trials continue in Europe and initial reports indicate 90-100% ulcer healing in patients suffering from duodenal ulcers after four weeks of 20 to 80 mg of racemic pantoprazole per day.
Racemic pantoprazole sodium is an orally active, potent, irreversible inhibitor of H.sup.+, K.sup.+ -ATPase. The compound is one of the class of compounds known as gastric "proton pump" inhibitors. These compounds are weak organic bases which diffuse passively from the plasma into the acid-containing intracellular canaliculi of gastric parietal cells. At the low pH found in the lumen of these canaliculi, the protonated compounds rearrange to form pyridinium sulfenamides, which react with sulfhydryl groups present on the ATPase localized in the membranes lining the intracellular canaliculi. The alkylation of the sulfhydryl inhibits the ability of the enzyme to catalyze the secretion of H.sup.+ into the lumen in exchange for K.sup.+ ions. This inhibition results in an overall reduction in hydrochloric acid secretion by the parietal cells into the cavity of the stomach, thus increasing intragastric pH. As a consequence of reduced acidity in the stomach, the activity of the proteolytic enzyme pepsin is also markedly decreased. Because the proton pump is the final step in acid production and the compounds of this class combine covalently with the associated H.sup.+, K.sup.+ -ATPase, a profound and prolonged inhibition of gastric acid secretion can be achieved.
The potency of pantoprazole in vitro as an inhibitor of aminopyrine uptake, which is an index of acid secretion in isolated gastric glands, is similar to that of omeprazole, a structurally related antiulcer agent. Pantoprazole is, however, more chemically stable under neutral and moderately acidic conditions than is omeprazole. This may increase pantoprazole's selectivity for the acid secreting parietal cells, where low pH conditions exist in the intracellular canaliculi. In intact animals, pantoprazole is active in inhibiting gastric acid secretion in both rats and dogs. Specifically, the intravenous and oral doses required to reduce endogenous acid secretion in pylorus-ligated rats by 50% are in the 1-3 .mu.mole/kg range. The calculated oral/intravenous (p.o./i.v.) ratio is approximately 2, suggesting good oral bioavailability. Racemic pantoprazole is also effective at doses less than 5 .mu.mole/kg in inhibiting exogenously stimulated acid secretion induced by a variety of agonists, indicating general activity of the drug in inhibiting acid secretion. The serum half-life of racemic pantoprazole is 1.1 to 1.5 hours in humans. Compared to omeprazole, racemic pantoprazole is a weaker inhibitor of hepatic drug metabolizing enzyme systems in intact rats and rat microsomal enzyme preparations. The intravenous LD.sub.50 values are 632 (rat) and 975 (mice) .mu.mole/kg; oral LD.sub.50 in mice is 1,893 and in rats &gt;2,467 .mu.mol/kg. The p.o./i.v. LD.sub.50 ratio of the compound in mice is about 2 and the rat LD.sub.50 values are at least two to three orders of magnitude greater than the corresponding doses required to produce half-maximal inhibition of endogenous acid secretion in this species.
Although no cardiovascular or obvious physical changes have been observed in humans on short-term administration of racemic pantoprazole, fasting serum gastrin levels are significantly elevated. This is cause for concern because prolonged elevated serum gastrin appears to be associated with diffuse and focal enterochromaffin-like cell hyperplasia and focal neoplasia (carcinoids) in rats. Larsson et al. Gastroenterology 90, 391-399 (1986)!. Thus, despite its advantages, some adverse effects of racemic pantoprazole may remain, including, but not limited to, some incidence of hepatocellular neoplasia and gastric carcinoids on long-term therapy, and headache, diarrhea and skin alterations on acute therapy. It would therefore be particularly desirable to find a compound with the advantages of the racemic mixture of pantoprazole which would not have the aforementioned disadvantages.